Intelligent hyaluronidase-responsive supramolecular nanoassemblies for programmable dual-drug delivery and NIR-II photothermal therapy of atherosclerosis

The development of controllable nanoplatforms with disease-specific responsiveness and programmable therapeutic functions is vital for treating complex cardiovascular diseases such as atherosclerosis. Herein, we present an intelligent, next-generation nanoplatform (HALA@Ag 2 S) that integrates enzyme-responsive dual-drug delivery with NIR-II imaging-guided photothermal therapy (PTT), enabling triple-stimuli synergy of enzyme, light, and multi-drug co-activation. This modular design enables stable nanoassemblies with high drug-loading capacity and selective disassembly in enzyme-rich plaque microenvironments, achieving controlled dual-drug release exceeding 80% within 72 h. Importantly, the unique integration of dual pharmacotherapy and NIR-II PTT within a single platform enables multi-level synergy: photothermal activation not only provides localized anti-inflammatory effects, but also promotes drug release and enhances plaque permeability, thereby amplifying the therapeutic benefits of both aspirin and lovastatin. In vitro, the platform facilitated targeted uptake, inhibited foam cell formation, and modulated cholesterol metabolism by regulating SREBP2 and ABCA1. In ApoE - / - mice, the combined therapy significantly reduced plaque area by 53%, improved lipid profiles, attenuated inflammatory cytokine expression, and enhanced vascular stability, as evidenced by increased collagen deposition and restored elastic fiber integrity. Compared with traditional nanotherapeutics, our green and biocompatible HA matrix combined with NIR-II photothermal modulation offers improved targeting, controlled release, and superior anti-inflammatory efficacy. This work demonstrates the potential of HALA@Ag 2 S as a solid alternative to current therapies and a paradigm for green, multi-modal strategies in complex cardiovascular disease.

开发具有疾病特异性反应性和可编程治疗功能的可控纳米平台对于治疗动脉粥样硬化等复杂心血管疾病至关重要。在此，我们提出了一种智能的下一代纳米平台（HALA@Ag 2 S），它将酶响应双药物递送与NIR-II成像引导光热疗法（PTT）相结合，实现酶、光和多药物共激活的三重刺激协同作用。这种模块化设计能够在富含酶的斑块微环境中实现具有高载药能力和选择性分解的稳定纳米组件，在72小时内实现超过80%的受控双药释放。重要的是，双重药物疗法和 NIR-II PTT 在单一平台中的独特整合可实现多层次协同作用：光热激活不仅提供局部抗炎作用，还促进药物释放并增强斑块通透性，从而放大阿司匹林和洛伐他汀的治疗效果。在体外，该平台通过调节 SREBP2 和 ABCA1 促进靶向摄取、抑制泡沫细胞形成并调节胆固醇代谢。在 ApoE - / - 小鼠中，联合疗法显着减少了 53% 的斑块面积，改善了脂质分布，减弱了炎症细胞因子的表达，并增强了血管稳定性，胶原蛋白沉积增加和弹性纤维完整性恢复就证明了这一点。与传统纳米治疗药物相比，我们的绿色和生物相容性透明质酸基质与 NIR-II 光热调节相结合，可提供改进的靶向性、控释性和卓越的抗炎功效。这项工作证明了 HALA@Ag 2 S 作为当前疗法的可靠替代品以及复杂心血管疾病绿色多模式策略范例的潜力。